Congenital diaphragmatic hernia (CDH) remains a difficult clinical problem with a mortality rate of nearly fifty percent. In CDH, the abdominal contents may herniate into the thoracic cavity, resulting in poor pulmonary development with resulting pulmonary hypoplasia. Even when the compression is reduced early in gestation, the lungs remain hypoplastic, suggesting a genetic component of the defect. Early lung development is remarkably conserved between humans and avian species. Therefore, a chick model was chosen for series of experiments designed to describe the function of four candidate factors- FT68, FT137, FT347, and FT399. These factors were described in our laboratory, and have been shown to be expressed in normal chick lung development. We will first study the temporal and spatial expression of these factors using in situ hybridization. Next, we will perform targeted lung infection with avian-specific retrovirus constructed with full-length, wild type candidate cDNA for overexpression and misexpression studies. The lungs will be analyzed at various developmental stages for gross morphology, histology, cytodifferention, and expression of known factors important in pulmonary development. If these factors are found to play a significant role in chick pulmonary development, the expression of human orthologs will be studied further with a library of archived normal and abnormal fetal and neonatal human lung samples. We hope that by better understanding the molecular events of normal and abnormal lung development, we will better understand pulmonary hypoplasia and to develop novel pharmacologic therapies for CDH. [unreadable] [unreadable] [unreadable]